Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer

NF-кB has been linked to doxorubicin resistance in breast cancer patients. NF-кB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-кB-dependent genes and the biological cons...

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Autores: Dalmases Massegú, Alba, 1982-, González González, Irene, Menendez Romero, Silvia, Arpí Llucià, Oriol, Corominas Torres, Josep Maria, Servitja Tormo, Sonia, Tusquets Trias de Bes, Ignacio, Chamizo, Cristina, Rincón, Raúl, Espinosa Blay, Lluís, Bigas Salvans, Anna, Eroles, Pilar, Furriol, Jessica, Lluch, Ana, Rovira Guerín, Ana, Albanell Mestres, Joan, Rojo, Federico
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2014
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/41974
Acceso en línea:http://hdl.handle.net/10230/41974
http://dx.doi.org/10.18632/oncotarget.1556
Access Level:acceso abierto
Palabra clave:Mama -- Càncer
Medicaments antineoplàstics
Duxorubicina
Proteïnes supressores de tumors
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spelling Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancerDalmases Massegú, Alba, 1982-González González, IreneMenendez Romero, SilviaArpí Llucià, OriolCorominas Torres, Josep MariaServitja Tormo, SoniaTusquets Trias de Bes, IgnacioChamizo, CristinaRincón, RaúlEspinosa Blay, LluísBigas Salvans, AnnaEroles, PilarFurriol, JessicaLluch, AnaRovira Guerín, AnaAlbanell Mestres, JoanRojo, FedericoMama -- CàncerMedicaments antineoplàsticsDuxorubicinaProteïnes supressores de tumorsNF-кB has been linked to doxorubicin resistance in breast cancer patients. NF-кB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-кB-dependent genes and the biological consequences are unclear. We studied NF-кB-dependent gene expression induced by doxorubicin in breast cancer cells and fresh human cancer specimens with different genetic backgrounds focusing on their p53 status. NF-кB-dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKβ-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-кB activation and p53 status was determined in a cohort of breast cancer patients treated with adjuvant doxorubicin-based chemotherapy. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-кB driven-gene transcription signature. Modulation of genes related with invasion, metastasis and chemoresistance (ICAM-1, CXCL1, TNFAIP3, IL8) were confirmed in additional doxorubicin-treated cell lines and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of the NF-кB-dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-кB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-кB/p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-кB-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.This work was supported by RD12/0036/0051 (J.A.), RD09/0076/0101, RD09/0076/0036, RD12/0036/0054 (A.B), RD12/0036/0070 (A. Ll), PI12/00680 (J.A.), PI12/01552 (F.R.), PI12/01421 (A.Ll.), 2009 SGR 321 (J.A.), FMM 9757/002 (F.R.), and the “Xarxa de Bancs de tumors sponsored by Pla Director d’Oncologia de Catalunya (XBTC). J.A. and F.R. are recipients of intensification program ISCIII/FEDER. We thank Fundació Cellex (Barcelona) for a generous donation to the Hospital del Mar Medical Oncology Service. We thank Millenium for generously providing MLN120BImpact Journals201920192014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/41974http://dx.doi.org/10.18632/oncotarget.1556reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésOncotarget. 2014 Jan;5(1):196-210© 2014 Dalmases et al.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedhttps://creativecommons.org/licenses/by/3.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/419742026-06-12T07:21:37Z
dc.title.none.fl_str_mv Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer
title Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer
spellingShingle Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer
Dalmases Massegú, Alba, 1982-
Mama -- Càncer
Medicaments antineoplàstics
Duxorubicina
Proteïnes supressores de tumors
title_short Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer
title_full Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer
title_fullStr Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer
title_full_unstemmed Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer
title_sort Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer
dc.creator.none.fl_str_mv Dalmases Massegú, Alba, 1982-
González González, Irene
Menendez Romero, Silvia
Arpí Llucià, Oriol
Corominas Torres, Josep Maria
Servitja Tormo, Sonia
Tusquets Trias de Bes, Ignacio
Chamizo, Cristina
Rincón, Raúl
Espinosa Blay, Lluís
Bigas Salvans, Anna
Eroles, Pilar
Furriol, Jessica
Lluch, Ana
Rovira Guerín, Ana
Albanell Mestres, Joan
Rojo, Federico
author Dalmases Massegú, Alba, 1982-
author_facet Dalmases Massegú, Alba, 1982-
González González, Irene
Menendez Romero, Silvia
Arpí Llucià, Oriol
Corominas Torres, Josep Maria
Servitja Tormo, Sonia
Tusquets Trias de Bes, Ignacio
Chamizo, Cristina
Rincón, Raúl
Espinosa Blay, Lluís
Bigas Salvans, Anna
Eroles, Pilar
Furriol, Jessica
Lluch, Ana
Rovira Guerín, Ana
Albanell Mestres, Joan
Rojo, Federico
author_role author
author2 González González, Irene
Menendez Romero, Silvia
Arpí Llucià, Oriol
Corominas Torres, Josep Maria
Servitja Tormo, Sonia
Tusquets Trias de Bes, Ignacio
Chamizo, Cristina
Rincón, Raúl
Espinosa Blay, Lluís
Bigas Salvans, Anna
Eroles, Pilar
Furriol, Jessica
Lluch, Ana
Rovira Guerín, Ana
Albanell Mestres, Joan
Rojo, Federico
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Mama -- Càncer
Medicaments antineoplàstics
Duxorubicina
Proteïnes supressores de tumors
topic Mama -- Càncer
Medicaments antineoplàstics
Duxorubicina
Proteïnes supressores de tumors
description NF-кB has been linked to doxorubicin resistance in breast cancer patients. NF-кB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-кB-dependent genes and the biological consequences are unclear. We studied NF-кB-dependent gene expression induced by doxorubicin in breast cancer cells and fresh human cancer specimens with different genetic backgrounds focusing on their p53 status. NF-кB-dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKβ-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-кB activation and p53 status was determined in a cohort of breast cancer patients treated with adjuvant doxorubicin-based chemotherapy. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-кB driven-gene transcription signature. Modulation of genes related with invasion, metastasis and chemoresistance (ICAM-1, CXCL1, TNFAIP3, IL8) were confirmed in additional doxorubicin-treated cell lines and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of the NF-кB-dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-кB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-кB/p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-кB-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.
publishDate 2014
dc.date.none.fl_str_mv 2014
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/41974
http://dx.doi.org/10.18632/oncotarget.1556
url http://hdl.handle.net/10230/41974
http://dx.doi.org/10.18632/oncotarget.1556
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Oncotarget. 2014 Jan;5(1):196-210
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/3.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/3.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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